[unreadable] [unreadable] Our long-term objectives are to understand the pathophysiology of streptococcal endocarditis which causes a significant health problem especially in immune compromised patients. Its diagnosis is often not made until late in disease process and the complication is serious and the cost for treatment is expensive. The traditional view of pathogenesis suggests that injury to endothelium predispose to non-bacterial thrombotic vegetation and infective endocarditis from a bacteremia episode. However, this model does not explain the occurrence of infective endocarditis in individuals without known valvular defects. Clinically, septic shock syndrome is related to excessive cytokine induction by endotoxin which causes intravascular coagulationand multiple organ failure. Our preliminary results have shown extraordinary induction of IFN-gamma and TNF-alpha by several oral streptococcal isolates implicated in endocarditis. In addition, we observed oral streptococci invaded human umblical vein endothelium via PAF-receptors which could be indirectly upregulated by inflammatory cytokines. These observations prompt us to hypothesize that excessive proinflammatory cytokines induced by oral streptococci might be a key host factor in bacterial invasion of endotheleal cells (EC) in the heart valves. We further hypothesize that streptococcal invasion to endothelial cells via PAF-receptors causes procoagulant change in EC. Due to the limited scope of this application, we propose to study three representative oral streptococci frequently recovered from endocarditis patients -S. mutans, S. oralis and S. sanguis. We shall determine the streptococci-induced host cytokine effects in promoting coagulation of EC by measuring tissue factor activities. The major cytokine in tissue factor induction will be identified and the synergy among proinflammatory cytokines (IL-1, TNF-alpha and IFN-gamma) and synergy between cytokines and bacterial invasion in promoting coagulation will be examined. We will also investigate the PAF-receptor dependent adherence/invasion mechanism and its relation to coagulation. The results of this study would help to clarify or identify the role of host cytokine induced by oral streptococci in pathogenesis of streptococcal endocarditis. We also hope to provide an insight regarding streptococcal invasion into EC and offer an alternative model for the initial formation of vegetation.